Diseases characterized by pathological immune responses include many diseases associated with significant mortality and morbidity, particularly autoimmune diseases, such as systemic lupus erythematosus (SLE), and transplantation-related diseases such as graft-versus-host disease (GVHD). Autoimmune diseases may generally be divided into two general types, namely systemic autoimmune diseases (e.g. SLE and scleroderma), and organ specific autoimmune diseases, such as multiple sclerosis, and diabetes.
Immunosuppressive drugs have been used for treatment or prevention of the rejection of transplanted organs and tissues (e.g., bone marrow, heart, kidney, liver); for treatment of autoimmune diseases or diseases that are most likely of autoimmune origin (e.g., rheumatoid arthritis, multiple sclerosis, myasthenia gravis, systemic lupus erythematosus, sarcoidosis, Crohn's disease, Behcet's Disease, pemphigus, uveitis and ulcerative colitis); treatment of some other non-autoimmune inflammatory diseases (e.g., long term allergic asthma control) as well as transplantation-related diseases (e.g. GVHD). However, immunosuppressive drug treatments can lead to many complications, and improved methods for dealing with pathological immune reactions are needed.
Approximately 30,000 patients annually in the U.S. and Europe undergo allogeneic bone marrow transplantation (BMT). In allogeneic bone marrow transplantation (alloBMT), the infusion of donor marrow into the patient's body entails the interaction of cells from two immune systems. Conditioning regimens for patients receiving allogeneic transplants allow the donor stem cells to engraft in the patient by suppressing the immune system. Once the donor's immune cells are established in the patient's body, they may recognize the patient's own tissue and cells, including any residual cancer cells, as being different or foreign. The immune system may then cause damage to certain organs such the liver, gastrointestinal tract or skin; this effect is known as graft-versus-host disease (GVHD).
As of today, GVHD prophylaxis comprises the combination of immunosuppressive drugs including a calcineurin inhibitor (CNI), cyclosporine or tacrolimus, and either methotrexate, mycophenolate mofetil (MMF), or sirolimus. However, acute GVHD still occurs in 35% to 70% of BMT patients who receive transplants from human leukocyte antigen (HLA)-matched siblings, and even more frequently in unrelated donor transplant recipients.
Although calcineurin inhibitors (CNIs) partially inhibit acute GVHD, they may impair immune reconstitution by inhibiting T-cell development and increasing the risk of disease relapse. Thus, patients with hematologic malignancies undergoing allogeneic BMT are in need of GVHD prophylaxis that would minimize the use of CNIs, prevent GVHD, and retain a functional immune system including a beneficial graft-versus-tumor effect.
U.S. Pat. Nos. 6,524,865, 6,607,722 and 7,109,031, and US patent applications 2010/0267137, 2010/01837365 relate to the production of immunosuppressive recipient dendritic cells, and contacting the dendritic cells with necrotic or apoptotic donor leukocytes, intended to reduce immune response to grafts or implants.
WO 2002/060376, to one of the inventors of the present application, discloses a method of treatment of a systemic autoimmune disease in a subject by administration of apoptotic and/or necrotic cells obtained from said subject.
WO 2006/117786, to one of the inventors of the present application, further discloses the use of a cell-preparation comprising dying or dead leukocytes for treatment of a disease characterized by a pathological immune response. The dying or dead leukocytes are obtained by inducing live leukocytes to adhere to a surface, and are capable of suppressing the pathological immune response in the subject.
A study by Mevorach et al., published after the priority date of the present application, examined infusion of donor mononuclear early apoptotic cells as prophylaxis for acute graft-versus-host disease (GVHD) after HLA-matched myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) from a related donor (Mevorach et al., ePub October 2013, Biol Blood Marrow Transplant).
During blood cell collection the use of anticoagulants is routine. During cell storage the use of anticoagulants has been reported to improve cell yield. Matsumoto et al. compared storage of peripheral blood stem cells (PBSC) under various conditions, including storage in University of Wisconsin (UW) solution and hypothermic preservation in autologous serum and the anticoagulant solution acid-citrate-dextrose (ACD) solution A. The survival of colony-forming unit granulocyte-macrophages (CFU-GM) was found to be significantly better in UW solution than the survival achieved with hypothermic preservation in autologous serum and ACD-A solution at 4° C. or cryopreservation at 80° C. (Matsumoto et al., 2002, Bone Marrow Transplantation, 30(11):777-784). Burger et al. disclosed that addition of heparin to plasma collected for cryopreservation of cells or addition of ACD-A prevented gelation of freezing solution (Burger, S. R. et al, 1996, Transfusion, 36: 798-801). WO 2003/006691 discloses a cell cryopreservation medium for CD34+ cells comprising heparin. Kao et. al. discloses storage of bone marrow cell, peripheral blood stem cell or peripheral blood mononuclear cell products at 4° C. or 20° C. in media comprising ACD-A and/or heparin (Kao et al., 2011, Transfusion, 51: 137-147). U.S. Pat. No. 6,489,311 discloses use of anticoagulants to prevent cell apoptosis.
There remains an unmet need for compositions and methods for treating or preventing immune disorders including autoimmune and inflammatory diseases and transplantation related diseases. For instance, GVHD, with an estimated incidence of 30%-70%, remains the main barrier for successful allogeneic blood or marrow transplantation, and the optimal approach for GVHD prophylaxis has not yet been established. In particular it is essential to obtain compositions and methods that prevent or ameliorate GVHD in a safe, reliable, reproducible and effective manner.